Hyaluronic acid is a well known mucopolysaccharide which is found in the joint tissue and vitreous humor of the eyes of mammals. It has been extracted from rooster combs and human umbilical cords and bacterial cultures such as those of hemolytic group A and C streptococci for various therapeutic purposes. The initial therapeutic use of this material was as a replacement for the liquid vitreous of the human eye to aid in ophthalmic surgery, especially in the treatment of retinal detachment. It has also found utility for the relief of trauma or irritation in joint tissue of mammals including humans by injection into the synovial fluid of the joint. It has been proposed that it be used both as a primary medicant and as an auxiliary with other joint medicines. An extensive discussion of its various utilities is found in U.S. Pat. No. 4,141,973 to Balazs. The use of hyaluronic acid alone and with cortisone in various animal joints, especially horses, is discussed in the "Effect of Intra-articular Injection of Hyaluronic Acid on the Clinical Symptoms of Osteoarthritis and on Granulation Tissue Formation" by Rydell et al. and appearing at pages 25 to 32 of the October, 1971 (Number 80) issue of Clinical Orthopaedics and Related Research. The use of hyaluronic acid in human joints is reported in the "Preliminary Clinical Assessment of Na Hyaluronate Injection into Human Arthritic Joints" by Peyron et al and appearing at pages 731 to 736 of the October 1974 (Volume 22, Number 8) of Pathologie Biologie. Finally, the use of hyaluronic acid in reducing fibrotic wound reactions is reported in the "Decreased Granulation Tissue Reaction After Installment of Hyaluronic Acid" by Rydell and appearing at pages 307 to 311 of Volume 41 of Acta Orthop. Scandinav.
The intra-articular use of hyaluronic acid in horse joints has been commercially promoted in connection with Pharmacia's Hylartil and Hylartin V product and Sterivet's Synacid product. However, the commercial attractiveness has been limited by the need to administer these products by injection into the affected joint.
A related material, a polysulfated glycosaminoglycan, has recently been introduced to the U.S. market by Luitpold Pharmaceuticals under the tradename Adequan.RTM. (also known in Europe as Arteparon) for the treatment of arthritic joints in horses. lnitially the recommended route of administration was intra-articular with a 250 mg injection each week for five weeks. A letter appearing at pages 446 and 447 of the April 1984 issue of Veterinary Medicine suggests that this material can be administered intramuscularly at approximately double the dosage on a four day interval for four to five weeks.
Polysulfated glycoaminoglycans have also been reported to stimulate the biosynthesis of hyaluronic acid in the synovial membranes of rabbit knee joints thus suggesting that although the mode of action may be different from hyaluronic acid the same conditions might be beneficially effected. Interestingly the report, "Influences of Sulfated Glycosaminoglycans on Biosynthesis of Hyaluronic Acid in Rabbit Knee Synovial Membrane", by Nishikawa et al and appearing at pages 146 to 153 of the July, 1985 issue (Volume 240) of Arch. Biochem. Biophys. indicates that hyaluronic acid itself has no such stimulatory effect.
This stimulatory agent has been reported to be effective if administered either intramuscularly to humans or subcutaneously to rats. The former effect is noted in "Vergleich von Glykosaminoglykanpolysulfat (Arteparon) und physiologischen Kochsalzloesung bei Arthrosen grosser Gelenke.Ergebnisse einer multizentrischen Duppelbindstudie" by Siegmeth et al and appearing at pages 223 to 228 of the July/August 1983 issue (Volume 42, Number 4) of Z. Rheumatol. The latter effect is discussed in "Die Tierexperimentelle Gonarthrose Der Ratte und Ihre Therapie mit Glyko-aminoglykan polysulfat" by Buchmann et al and appearing at pages 100 to 107 of the 1985 issue (Volume 44, Number 3) of Z. Rheumatol.
This stimulatory agent has also been reported to have a broad range of lower molecular weights. In the "Influence of a Glycosaminoglycan Polysulfate (Arteparon) on Lysosomal Enzyme Release from Human Polymorphonuclear Leukocytes" by Mikulikova and appearing at pages 50 to 53 of the March/April 1982 issue (Volume 41, Number 2) of Z. Rheumatol is an indication that Arteparon can be fractionated into portions having molecular weights between 3000 and 17,000. In "Polysulfated Glycosaminoglycan: a New Intra-articular Treatment for Equine Lameness" by Hamm, Goldman and Jones appearing at pages 811 to 816 of the June, 1984 issue of Veterinary Medicine Adequan is reported to have an approximate molecular weight of 10,000. In this regard, one of the coauthors, Dr. Goldman, is associated with Lutipold Pharmaceuticals, the U.S. distributor of this product.
The direct use of hyaluronic acid has been found to be effective at lower dosages than this polysulfated glycosaminoglycan, which stimulates hyaluronic acid production in joint tissue. For instance the Adequan polysulfated glycosaminoglycan is sold with a dosage recommendation of 250 mg for intra-articular administration to horses whereas Pharmacia markets hyaluronic acid under the name Hylartil with a recommended dosage for intraarticular administration of 20 mg. Although the Adequan product has been reported to be effective when administered intramuscularly at double the dose (500 mg) a similar effect was not expected for the high molecular weight sodium hyaluronate.
It was not expected that sodium hyaluronate would be amenable to remote administration because its primary action was thought to be lubrication and because of its molecular weight which is typically well in excess of 1.times.10.sup.6 daltons. It was expected that molecules of such a molecular weight would be too large to transfer through mammalian tissue to the remote site of trauma. Thus, it was assumed that effective amounts of sodium hyaluronate could not be transported through the body of a mammal to the site of action upon the remote administration of reasonable sized doses.
It has now been found that the remote administration of hyaluronic acid is effective in reducing the pain and swelling of traumatized or irritated mammalian tissue, particularly joint tissue.